Mechanical ventilation is essential in acute respiratory failure, but carries the risk of ventilator-induced lung injury (VILI). Pulmonary protective ventilation with low tidal volumes of 4–8 mL/kg predicted body weight improved outcomes in acute respiratory distress syndrome (ARDS), but does not account for the heterogeneity of injured lungs or the variability of patient physiology. Mechanisms of VILI include barotrauma, volutrauma, ateletrauma, and biotrauma, which cause diaphragmatic dysfunction and secondary organ damage. Physiological tools such as esophageal manometry, electrical impedance tomography, and lung ultrasound allow real-time assessment of lung stress, regional ventilation, recruitment, and patient effort. These help to individualize ventilation, prevent overdistension and collapse, limit harmful pressures and volumes, and maintain gas exchange with hemodynamic stability. Advances such as closed-loop ventilation systems, adaptive algorithms, and computational modeling make it possible to predict harmful mechanical patterns. Physiology-driven personalized mechanical ventilation moves care from protocols to patient-centeredness to reduce VILI and improve outcomes in the critically ill.